US5981485A - Human growth hormone aqueous formulation - Google Patents

Human growth hormone aqueous formulation Download PDF

Info

Publication number
US5981485A
US5981485A US08891823 US89182397A US5981485A US 5981485 A US5981485 A US 5981485A US 08891823 US08891823 US 08891823 US 89182397 A US89182397 A US 89182397A US 5981485 A US5981485 A US 5981485A
Authority
US
Grant status
Grant
Patent type
Prior art keywords
formulation
growth hormone
aqueous
mg
human growth
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08891823
Inventor
Barbara H. O'Connor
James Q. Oeswein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Original Assignee
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/27Growth hormone [GH] (Somatotropin)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183Amino acids, e.g. glycine, EDTA or aspartame
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Abstract

A stable pharmaceutically acceptable aqueous formulation containing human growth hormone, a buffer, a non-ionic surfactant, and, optionally, a neutral salt, mannitol, or, a preservative, is disclosed. Also disclosed are associated means and methods for preparing, storing, and using such formulations.

Description

This application is a continuation of application Ser. No. 08/117,156, filed Sep. 14, 1993 now U.S. Pat. No. 5,763,394, which is a 371 of PCT/US93/07149 filed Jul. 29, 1993.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical formulations containing human growth hormone (hGH) and to methods for making and using such formulations. More particularly, this invention relates to such pharmaceutical formulations having increased stability in aqueous formulation.

BACKGROUND OF THE INVENTION

Human growth hormone formulations known in the art are all lyophilized preparations requiring reconstitution. Per vial, Protropin® hGH consists of 5 mg hGH, 40 mg mannitol, 0.1 mg monobasic sodium phosphate, 1.6 mg dibasic sodium phosphate, reconstituted to pH 7.8 (Physician's Desk Reference, Medical Economics Co., Orawell, N.J., p. 1049, 1992). Per vial, Humatrope® hGH consists of 5 mg hGH, 25 mg mannitol, 5 mg glycine, 1.13 mg dibasic sodium phosphate, reconstituted to pH 7.5 (Physician's Desk Reference, p. 1266, 1992).

For a general review for growth hormone formulations, see Pearlman et al., Current Communications in Molecular Biology, eds. D. Marshak and D. Liu, pp. 23-30, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. Other publications of interest regarding stabilization of proteins are as follows.

U.S. Pat. No. 4,297,344 discloses stabilization of coagulation factors II and VIII, antithrombin III, and plasminogen against heat by adding selected amino acids such as glycine, alanine, hydroxyproline, glutamine, and aminobutyric acid, and a carbohydrate such as a monosaccharide, an oligosaccharide, or a sugar alcohol.

U.S. Pat. No. 4,783,441 discloses a method for the prevention of denaturation of proteins such as insulin in aqueous solution at interfaces by the addition of up to 500 ppm surface-active substances comprising a chain of alternating, weakly hydrophilic and weakly hydrophobic zones at pH 6.8-8.0.

U.S. Pat. No. 4,812,557 discloses a method of stabilization of interleukin-2 using human serum albumin.

European Patent Application Publication No. 0 303 746 discloses stabilization of growth promoting hormones with polyols consisting of non-reducing sugars, sugar alcohols, sugar acids, pentaerythritol, lactose, water-soluble dextrans, and Ficoll, amino acids, polymers of amino acids having a charged side group at physiological pH, and choline salts.

European Patent Application Publication No. 0 211 601 discloses the stabilization of growth promoting hormones in a gel matrix formed by a block copolymer containing polyoxyethylene-polyoxypropylene units and having an average molecular weight of about 1,100 to about 40,000.

European Patent Application Publication No. 0 193 917 discloses a biologically active composition for slow release characterized by a water solution of a complex between a protein and a carbohydrate.

Australian Patent Application No. AU-A-30771/89 discloses stabilization of growth hormone using glycine and mannitol.

U.S. Pat. No. 5,096,885 (which is not prior art) discloses a formulation of hGH for lyophilization containing glycine, mannitol, a non-ionic surfactant, and a buffer. The instant invention provides an unexpectedly stabilized aqueous formulation in the absence of glycine.

hGH undergoes several degradative pathways, especially deamidation, aggregation, clipping of the peptide backbone, and oxidation of methionine residues. Many of these reactions can be slowed significantly by removal of water from the protein. However, the development of an aqueous formulation for hGH has the advantages of eliminating reconstitution errors, thereby increasing dosing accuracy, as well as simplifying the use of the product clinically, thereby increasing patient compliance. Thus, it is an objective of this invention to provide an aqueous hGH formulation which provides acceptable control of degradation products, is stable to vigorous agitation (which induces aggregation), and is resistant to microbial contamination (which allows multiple use packaging).

SUMMARY OF THE INVENTION

One aspect of the invention is a stable, pharmaceutically acceptable, aqueous formulation of human growth hormone comprising human growth hormone, a buffer, a non-ionic surfactant, and optionally, a neutral salt, mannitol, and a preservative.

A further aspect of the invention is a method of preventing denaturation of human growth hormone aqueous formulations comprising mixing human growth hormone and a non-ionic surfactant in the range of 0.1-5% (w/v) (weight/volume). In yet another aspect of the invention, this stabilized formulation is stored for 6-18 months at 2-8° C.

DESCRIPTION OF THE FIGURES

FIG. 1 is a size exclusion chromatogram of aqueous growth hormone formulation stored for 28 days at 40° C. (i.e., thermally stressed) and for one year at 5° C. (i.e., recommended conditions for storage).

FIG. 2 is a plot of Arrhenius rate analysis of growth hormone aggregation in aqueous formulation.

FIG. 3 is an anion exchange chromatogram comparing a thermally stressed (40° C.) aqueous formulation hGH sample with an aqueous formulation hGH sample stored under recommended conditions (2-8° C.) for one year.

FIG. 4 is a plot of Arrhenius rate analysis of hGH deamidation in aqueous formulation.

FIG. 5 is a graph of the percentage monomer present in the various formulations where mannitol has been substituted with a neutral salt.

DETAILED DESCRIPTION OF THE INVENTION

A. Definitions

The following terms are intended to have the indicated meanings denoted below as used in the specification and claims.

The terms "human growth hormone" or "hGH" denote human growth hormone produced by methods including natural source extraction and purification, and by recombinant cell culture systems. Its sequence and characteristics are set forth, for example, in Hormone Drugs, Gueriguian et al., U.S.P. Convention, Rockville, Md. (1982). The terms likewise cover biologically active human growth hormone equivalents, e.g., differing in one or more amino acid(s) in the overall sequence. Furthermore, the terms used in this application are intended to cover substitution, deletion and insertion amino acid variants of hGH, or posttranslational modifications. Two species of note are the 191 amino acid native species (somatropin) and the 192 amino acid N-terminal methionine (met) species (somatrem) commonly obtained recombinantly.

The term "pharmaceutically effective amount" of hGH refers to that amount that provides therapeutic effect in an administration regimen. The compositions hereof are prepared containing amounts of hGH at least about 0.1 mg/ml, upwards of about 10 mg/ml, preferably from about 1 mg/ml to about 20 mg/ml, more preferably from about 1 mg/ml to about 5 mg/ml. For use of these compositions in administration to human patients suffering from hypopituitary dwarfism, for example, these compositions contain from about 0.1 mg/ml to about 10 mg/ml, corresponding to the currently contemplated dosage regimen for the intended treatment. The concentration range is not critical to the invention, and may be varied by the clinician.

B. General Methods

The instant invention has no requirement for glycine. Glycine is an optional component of the aqueous formulation, although with less advantage in the aqueous formulations hereof compared with those formulations that are lyophilized for later reconstitution. Amounts of glycine will range from 0 mg/ml to about 7 mg/ml.

Non-ionic surfactants include a polysorbate, such as polysorbate 20 or 80, etc., and the poloxamers, such as poloxamer 184 or 188, Pluronic® polyols, and other ethylene/polypropylene block polymers, etc. Amounts effective to provide a stable, aqueous formulation will be used, usually in the range of from about 0.1% (w/v) to about 5% (w/v), more preferably, 0.1% (w/v) to about 1% (w/v). The use of non-ionic surfactants permits the formulation to be exposed to shear and surface stresses without causing denaturation of the protein. For example, such surfactant-containing formulations are employed in aerosol devices such as those used in pulmonary dosing and needleless jet injector guns.

Buffers include phosphate, Tris, citrate, succinate, acetate, or histidine buffers. Most advantageously, the buffer is in the range of about 2 mM to about 50 mM. The preferred buffer is a sodium citrate buffer.

A preservative is included in the formulation to retard microbial growth and thereby allow "multiple use" packaging of the hGH. Preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, benzalconium chloride, and benzethonium chloride. The preferred preservatives include 0.2-0.4% (w/v) phenol and 0.7-1% (w/v) benzyl alcohol.

Suitable pH ranges, adjusted with buffer, for aqueous hGH formulation are from about 4 to 8, more preferably about 5.5 to about 7, most advantageously 6.0. Preferably, a buffer concentration range is chosen to minimize deamidation, aggregation, and precipitation of hGH.

Mannitol may optionally be included in the aqueous hGH formulation. The preferred amount of mannitol is about 5 mg/ml to about 50 mg/ml. As an alternative to mannitol, other sugars or sugar alcohols are used, such as lactose, trehalose, stachiose, sorbitol, xylitol, ribitol, myoinositol, galactitol, and the like.

Neutral salts such as sodium chloride or potassium chloride are optionally used in place of sugars or sugar alcohols. The salt concentration is adjusted to near isotonicity, depending on the other ingredients present in the formulation. For example, the concentration range of NaCl may be 50-200 mM, depending on the other ingredients present.

In a preferred embodiment, the formulation of the subject invention comprises the following components at pH 6.0.

______________________________________Ingredient           Quantity (mg)______________________________________hGH                  5  Sodium Chloride 8.8  Polysorbate 20 2.0  Sodium citrates 2.5  Phenol 2.5  Sterile water 1 ml______________________________________

It will be understood that the above quantities are somewhat flexible within ranges, as set forth in more detail above, and that the materials are interchangeable within the component categories. That is, polysorbate 80, or a poloxamer, may be substituted for polysorbate 20, a succinate or acetate buffer could instead be employed, and alternative preservatives and different pHs could be used. In addition, more than one buffering agent, preservative, sugar, neutral salt, or non-ionic surfactant may be used. Preferably, the formulation is isotonic and sterile.

In general, the formulations of the subject invention may contain other components in amounts not detracting from the preparation of stable forms and in amounts suitable for effective, safe pharmaceutical administration. For example, other pharmaceutically acceptable excipients well known to those skilled in the art may form a part of the subject compositions. These include, for example, various bulking agents, additional buffering agents, chelating agents, antioxidants, cosolvents and the like; specific examples of these could include trimethylamine salts ("Tris buffer"), and disodium edetate.

EXPERIMENTAL EXAMPLES

A. Assay Methods

Anion exchange chromatography (HPIEC) was run on a TSK DEAE 5PW column (1.0×7.5 cm) at 45° C. with a flow rate of 0.5 ml/min. The column was equilibrated in 50 mM potassium phosphate, pH 5.5, containing 10% (w/v) acetonitrile. Elution was performed using a 25 minute gradient from 50-100 mM potassium phosphate, pH 5.5 with constant 10% (w/v) acetonitrile. The column load was 83 μg of protein. Detection was at 230 nM.

Nondenaturing size exclusion chromatography was run on a TSK 2000 SWXL column in 50 mM sodium phosphate, pH 7.2 containing 150 mM sodium chloride. The flow rate was 1 ml/min, with a 50-75 μg column load and detection at either 214 and 280 nm.

Denaturing size exclusion chromatography was run on a Zorbax GF250 column in 200 mM sodium phosphate, pH 6.8-7.2/0.1% SDS. The flow rate was 1.0 ml/minute, with a with a 50-75 μg column load and detection at either 214 and 280 nm.

B. Formulation Preparation

In general, aqueous hGH formulation samples for analysis in these experimental examples were prepared by buffer exchange on a gel filtration column. The elution buffer contained either sodium chloride or mannitol, buffer and the non-ionic surfactant in their final ratios. This resulting solution was diluted to a desired hGH concentration and the preservative was added. The solution was sterile filtered using a sterilized membrane filter (0.2 micron pore size or equivalent) and filled into sterile 3 cc type 1 glass vials, stoppered and sealed with aqueous-type butyl rubber stoppers and aluminum flip-off type caps.

The aqueous hGH formulation used in the experimental examples consisted of 5.0 mg somatropin (Genentech, Inc.), 45.0 mg mannitol, 2.5 mg phenol, 2.0 mg polysorbate 20, and 2.5 mg sodium citrate, pH 6.0, per ml of solution. The lyophilized formulation used as a reference for comparison in the examples consisted of 5.0 mg somatropin, 1.7 mg glycine, 45.0 mg mannitol, 1.7 mg sodium phosphate, 9 mg benzyl alcohol per ml sterile solution after reconstitution.

C. Example I

Chemical Stability of the Aqueous Formulation

Vials of the hGH aqueous formulation (lots 12738/55-102 and 12738/55-105) were incubated at either recommended storage temperatures of 2-8° C., or elevated storage temperatures of 15° C., or 25° C., and then removed at various time points and assayed for changes in pH, color and appearance, and protein concentration. In addition, samples were incubated at 40° C. in order to study degradation patterns under extreme stress conditions. Degradation patterns for the aqueous formulation were also compared to the known degradation patterns for lyophilized growth hormone.

After storage at 2-8° C. for up to one year, the aqueous formulation showed insignificant changes in pH, color and appearance, and protein concentration. Nondenaturing size exclusion HPLC performed on samples stored for up to one year at 2-8° C. showed no significant aggregation of the drug product (FIG. 1). This result is unexpected in light of the teaching of U.S. Pat. No. 5,096,885 that glycine contributes to preventing aggregation in the lyophilized preparation.

At temperatures above 8° C., little or no changes in pH or protein concentration were observed over time. Visual inspection revealed an increase in opalescence with time for samples stored at 40° C. This change was minimal during storage at 15-25° C. and has not been observed during 2-8° C. storage.

The amount of degradation product was calculated as an area percentage of the total hGH area of the chromatogram. The rate constant for each reaction was then calculated by subtracting the percentage of degradation product from 100%, taking the log10, and plotting against the time in days. The slope of a straight line to fit these data was used as the reaction constant (k). Arrhenius analysis was done by plotting the natural logarithm (ln) of the absolute value of each calculated reaction rate constant at 15, 25, and 40° C. as a function of the inverse absolute temperature and then extrapolating to 5° C. Arrhenius and real time rate analysis (FIG. 2) of data from the size exclusion HPLC indicate that the amount of growth hormone aggregation after 18 months of storage will be less than 1% (w/v).

Anion exchange HPLC analysis performed on the aqueous hGH formulation stored at 40° C. indicated an increase in acidic peaks over 28 days (FIG. 3). Three of these peaks, eluting at about 16, 17.5, and 26 minutes, were produced by hGH deamidation at positions 149, 152, and 149 plus 152. Arrhenius and real time rate analysis (FIG. 4) of data from this method, were plotted as described above, and indicate that the amount of deamidated hGH in these lots after 18 months of storage at 2-8° C. will be about 9% (w/v). This includes an initial amount of about 2.4% (w/v) deamidated hGH at time zero. Values as high as 15% (w/v) deamidation have been reported for other hGH products (Larhammar, H., et al., (1985) Int. J. Pharmaceutics 23:13-23). Although the rate of deamidation is faster in the aqueous state, this rate is minimized at pH 6.0 and below.

D. Example II

Physical Stability of the Aqueous Formulation

Each of six vials of lyophilized growth hormone were reconstituted with 1 ml bacteriostatic water for injection (BWFI) U.S.P. After dissolving, the contents were transferred to 3 cc vials, stoppered, and capped to provide the same configuration as that for the aqueous formulation. The six vials of the hGH aqueous formulation and six vials of reconstituted lyophilized hGH were vigorously shaken top to bottom in a horizontal fashion on a Glas-Col Shaker-in-the-Round at 240 jolts per minute using a stroke setting of 2.5, giving a horizontal displacement of 8±1 cm for up to 24 hours at room temperature to assess the effects of agitation on physical stability of the hGH aqueous formulation. All twelve samples were placed in a straight line on the shaker to assure that they were all exposed to the same force for each formulation. Two vials were removed for assays at 30 minutes, 6 hours, and 24 hours.

The results are displayed in Table I. Agitation produced very little change in the visual clarity of the aqueous formulation. There was no change in the content of total growth hormone monomer as detected by a nondenaturing size exclusion HPLC assay. This assay detects noncovalent aggregates, which are completely dispersed by SDS in a denaturing size exclusion HPLC assay.

By comparison, these results also demonstrated that the reconstituted lyophilized product was more sensitive to treatment, even after only 30 minutes of shaking. This sensitivity is typical for all currently available formulations of hGH, other than the aqueous formulation of the instant invention. The inclusion of the non-ionic surfactant is the most important factor in preventing this phenomenon from occurring.

              TABLE I______________________________________Effects of Agitation at Room Temperature on hGH  Aqueous Formulation vs. Reconstituted Lyophilized Formulation                      %      %     %    HPSEC Soluble Total.sup.1  Sample Color/Appearance Monomer Protein Monomer______________________________________Unshaken  Aqueous clear/colorless 99.7 ND ND  Aqueous clear/colorless 99.9 ND ND  Lyophilized clear/colorless 99.0 100 99.0  Lyophilized clear/colorless ND ND ND  Shaken  0.5 hr  Aqueous very slightly 99.9 100 99.9   opalescent/colorless  Aqueous very slightly 100.0   100 100.0   opalescent/colorless  Lyophilized slightly opalescent/ 93.6 100 93.6   colorless  Lyophilized clear/colorless 92.8 100 92.8  Shaken  6 hr  Aqueous slightly opalescent/ 99.9 100 99.9   colorless  Aqueous opalescent/colorless 99.8 100 99.8  Lyophilized very 80.5  73 58.8   opalescent/yellow to   brown  Lyophilized very 72.7 61.7 44.9   opalescent/yellow to   brown  Shaken  24 hr  Aqueous slightly 99.8 100 99.8   opalescent/colorless  Aqueous clear/colorless 99.8 ND ND  Lyophilized very cloudy/yellow to 60.6 21.5 13.0   brown  Lyophilized very cloudy/yellow to 56.7 14.8  8.4   brown______________________________________ .sup.1 Total monomer = (% monomer × % soluble protein)/100

E. Example III

Preservative Effectiveness in the Aqueous Formulation

Samples of hGH aqueous formulation were subjected to bacterial challenge according to an abbreviated challenge using the standard U.S.P. test. In this test, a suspension of either E. coli or S. aureus was added to an aliquot of hGH aqueous formulation to give a final concentration of bacteria between 105 to 106 CFU/ml. Viable bacteria remaining in the tubes were counted immediately and after 4 and 24 hours incubation at 20-25° C. The percentage change in the concentration of the microorganisms during the challenge was calculated according to the following equation: ##EQU1##

The results of this experiment indicated that for two species of bacteria, concentrations of viable bacteria were reduced to less than 0.01% of the initial concentrations after 24 hours.

F. Example IV

Substitution of Mannitol with Salt

In this experiment aqueous formulations of hGH were compared that varied in concentrations of salt, mannitol, and non-ionic surfactant. All formulations contained 5 mg/ml hGH/0.25% (w/v) phenol/10 mM sodium citrate, pH 6.0. Samples were stored 3-4 months at 2-8° C. FIG. 5 indicates the percentage monomer present in the indicated formulations. The Table below indicates the composition of each formulation. These results demonstrate the unexpected stability of hGH in a formulation in which mannitol has been substituted with a neutral salt in the presence of a surfactant.

              TABLE 3______________________________________Formulations Tested in FIG. 5  Formulation #      Composition______________________________________42               0.1% (w/v) polysorbate 20   50 mM mannitol  47 0.1% (w/v) poloxamer /188   0.1M NaCl  51 0.5% (w/v) polysorbate 20   50 mM mannitol  52 0.1% (w/v) poloxamer 188   50 mM mannitol  53 0.1% (w/v) poloxamer 184   50 mM mannitol  60 0.2% (w/v) polysorbate 20   0.1M NaCl  61 0.2% (w/v) polysorbate 20   0.05M NaCl  62 0.2% (w/v) polysorbate 20   0.15M NaCl  63 0.2% (w/v) polysorbate 20   50 mM mannitol______________________________________

Claims (8)

We claim:
1. An aqueous formulation of human growth hormone comprising:
a) 1 mg/ml to 20 mg/ml human growth hormone;
b) buffer providing pH 5.5 to pH 7;
c) 0.1% w/v to 1% w/v nonionic surfactant; and
d) 50 nM to 200 nM neutral salt, wherein said aqueous formulation is free of glycine and mannitol and is capable of storage for 6 to 18 months at 2 to 8° C.
2. The formulation of claim 1 wherein said nonionic surfactant is a poloxamer.
3. The formulation of claim 1 wherein said nonionic surfactant is a polysorbate.
4. The formulation of claim 1 wherein said neutral salt is sodium chloride.
5. The formulation of claim 1 wherein said buffer is selected from the group consisting of citrate, phosphate, Tris, succinate, and histidine buffers.
6. The formulation of claim 1 further comprising a preservative.
7. The formulation of claim 6 wherein said preservative is selected from the group consisting of phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, benzalkonium chloride, and benzethonium chloride.
8. A method of making a storage stable aqueous formulation of human growth hormone comprising mixing said human growth hormone into an aqueous, pharmaceutically acceptable vehicle which includes
a) 1 mg/ml to 20 mg/ml of said human growth hormone;
b) buffer providing pH 5.5 to pH 7;
c) 0.1% w/v to 1% w/v nonionic surfactant; and
d) 50 nM to 200 nM neutral salt;
wherein said aqueous, pharmaceutically acceptable vehicle is free of glycine and mannitol and is capable of storage for 6 to 18 months at 2 to 8° C.
US08891823 1997-07-14 1997-07-14 Human growth hormone aqueous formulation Expired - Lifetime US5981485A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08891823 US5981485A (en) 1997-07-14 1997-07-14 Human growth hormone aqueous formulation

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US08891823 US5981485A (en) 1997-07-14 1997-07-14 Human growth hormone aqueous formulation
US09344225 US6448225B2 (en) 1988-04-15 1999-06-25 Human growth hormone aqueous formulation
US10186775 US20030013653A1 (en) 1988-04-15 2002-07-01 Human growth hormone aqueous formulation
US11199314 US20050272657A1 (en) 1988-04-15 2005-08-08 Human growth hormone aqueous formulation
US11529677 US20070027083A1 (en) 1988-04-15 2006-09-28 Human growth hormone aqueous formulation
US12321084 US20090163419A1 (en) 1988-04-15 2009-01-15 Human growth hormone aqueous formulation
US13150911 US20110230408A1 (en) 1988-04-15 2011-06-01 Human growth hormone aqueous formulation
US13772773 US20130165378A1 (en) 1997-07-14 2013-02-21 Method of treating human growth hormone mediated condition

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
US08117156 Continuation
US08117156 Continuation US5763394A (en) 1988-04-15 1993-07-29 Human growth hormone aqueous formulation
PCT/US1993/007149 Continuation WO1994003198A1 (en) 1992-07-31 1993-07-29 Human growth hormone aqueous formulation

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09344225 Continuation US6448225B2 (en) 1988-04-15 1999-06-25 Human growth hormone aqueous formulation

Publications (1)

Publication Number Publication Date
US5981485A true US5981485A (en) 1999-11-09

Family

ID=25398881

Family Applications (8)

Application Number Title Priority Date Filing Date
US08891823 Expired - Lifetime US5981485A (en) 1997-07-14 1997-07-14 Human growth hormone aqueous formulation
US09344225 Expired - Fee Related US6448225B2 (en) 1988-04-15 1999-06-25 Human growth hormone aqueous formulation
US10186775 Abandoned US20030013653A1 (en) 1988-04-15 2002-07-01 Human growth hormone aqueous formulation
US11199314 Abandoned US20050272657A1 (en) 1988-04-15 2005-08-08 Human growth hormone aqueous formulation
US11529677 Abandoned US20070027083A1 (en) 1988-04-15 2006-09-28 Human growth hormone aqueous formulation
US12321084 Abandoned US20090163419A1 (en) 1988-04-15 2009-01-15 Human growth hormone aqueous formulation
US13150911 Abandoned US20110230408A1 (en) 1988-04-15 2011-06-01 Human growth hormone aqueous formulation
US13772773 Abandoned US20130165378A1 (en) 1988-04-15 2013-02-21 Method of treating human growth hormone mediated condition

Family Applications After (7)

Application Number Title Priority Date Filing Date
US09344225 Expired - Fee Related US6448225B2 (en) 1988-04-15 1999-06-25 Human growth hormone aqueous formulation
US10186775 Abandoned US20030013653A1 (en) 1988-04-15 2002-07-01 Human growth hormone aqueous formulation
US11199314 Abandoned US20050272657A1 (en) 1988-04-15 2005-08-08 Human growth hormone aqueous formulation
US11529677 Abandoned US20070027083A1 (en) 1988-04-15 2006-09-28 Human growth hormone aqueous formulation
US12321084 Abandoned US20090163419A1 (en) 1988-04-15 2009-01-15 Human growth hormone aqueous formulation
US13150911 Abandoned US20110230408A1 (en) 1988-04-15 2011-06-01 Human growth hormone aqueous formulation
US13772773 Abandoned US20130165378A1 (en) 1988-04-15 2013-02-21 Method of treating human growth hormone mediated condition

Country Status (1)

Country Link
US (8) US5981485A (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387711B1 (en) * 2000-08-11 2002-05-14 Quest Diagnostics Investments Incorporated Liquid intact parathyroid hormone (PTH) standards
GB2371227A (en) * 2001-01-10 2002-07-24 Grandis Biotech Gmbh Crystallisation - resistant aqueous growth hormone formulations
US20020160353A1 (en) * 2000-08-11 2002-10-31 Quest Diagnostics Investments Incorporated Preservative solutions
WO2003079991A2 (en) * 2002-03-20 2003-10-02 Advanced Inhalation Research, Inc. Method for administration of growth hormone via pulmonary delivery
WO2004060310A2 (en) 2002-12-31 2004-07-22 Altus Pharmaceuticals Inc. Human growth hormone crystals and methods for preparing them
US20040158046A1 (en) * 2001-05-14 2004-08-12 Loh Yoke Peng Modified growth hormone
WO2005063298A1 (en) 2003-12-23 2005-07-14 Pharmacia Corporation Stable growth hormone liquid formulation
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
US20050209144A1 (en) * 1998-04-28 2005-09-22 Nps Allelix Corporation Protein formulations
US20060039987A1 (en) * 2002-03-20 2006-02-23 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
US20060135427A1 (en) * 2004-12-22 2006-06-22 Ambrx, Inc. Formulations of human growth hormone comprising a non-naturally encoded amino acid
US20060165733A1 (en) * 2002-07-09 2006-07-27 Michael Betz Liquid formulations with high concentration of hunan growth hormone (hgh) comprising phenol
US20090023629A1 (en) * 2005-12-23 2009-01-22 Altus Pharmaceuticals Inc. Compositions comprising polycation-complexed protein crystals and methods of treatment using them
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins
US8420779B2 (en) 2007-05-22 2013-04-16 Amgen Inc. Compositions and methods for producing bioactive fusion proteins
US20150118255A1 (en) * 2012-03-30 2015-04-30 Hanmi Science Co., Ltd Liquid formulation of highly concentrated long-acting human growth hormone conjugate
US9238878B2 (en) 2009-02-17 2016-01-19 Redwood Bioscience, Inc. Aldehyde-tagged protein-based drug carriers and methods of use
US9540438B2 (en) 2011-01-14 2017-01-10 Redwood Bioscience, Inc. Aldehyde-tagged immunoglobulin polypeptides and methods of use thereof
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070179096A1 (en) * 1996-04-24 2007-08-02 Novo Nordisk A/S Pharmaceutical Formulation
US20030162711A1 (en) * 1996-04-24 2003-08-28 Soren Bjorn Pharmaceutical formulation
US5981485A (en) * 1997-07-14 1999-11-09 Genentech, Inc. Human growth hormone aqueous formulation
US20070065469A1 (en) * 2002-07-09 2007-03-22 Michael Betz Liquid formulations with high concentration of human growth hormone (high) comprising glycine
CN103040732B (en) * 2003-02-10 2015-04-01 伊兰药品公司 Immunoglobulin formulation and method of preparation thereof
US20090136538A1 (en) * 2006-05-22 2009-05-28 Jan Jezek Stable vaccine formulation
EP2264162A1 (en) * 2005-07-02 2010-12-22 Arecor Limited Stable aqueous systems comprising proteins
CN101505789A (en) * 2006-07-06 2009-08-12 株式会社大熊 A stable liquid formulation of human growth hormone
GB0700523D0 (en) * 2007-01-11 2007-02-21 Insense Ltd The Stabilisation Of Proteins
CA2726824A1 (en) * 2008-05-01 2009-11-05 Arecor Limited Protein formulation
EP2328607A1 (en) * 2008-07-16 2011-06-08 Arecor Limited Stable formulation of a therapeutic protein
EP2341940A1 (en) * 2008-07-16 2011-07-13 Arecor Limited The stabilisation of proteins
ES2383347T3 (en) * 2009-07-15 2012-06-20 Teva Pharmaceutical Industries, Ltd. Reduced volume formulation of glatiramer acetate and methods of administration
US8920373B2 (en) 2009-07-15 2014-12-30 Teva Pharmaceutical Industries, Ltd. Reduced volume formulation of glatiramer acetate and methods of administration
CN107050423A (en) 2009-08-20 2017-08-18 医达研究发展有限公司 Low frequency glatiramer acetate therapy
KR101337797B1 (en) 2010-07-14 2013-12-06 한미사이언스 주식회사 A liquid formulation of long acting human growth hormone conjugate
US20140194356A1 (en) * 2011-07-25 2014-07-10 Sandoz Ag Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein
CN102302446B (en) * 2011-09-08 2013-04-17 安徽安科生物工程(集团)股份有限公司 Recombinant human growth hormone injection capable of being directly used

Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928137A (en) * 1971-10-20 1975-12-23 Mallinckrodt Inc Reagent formulation for uric acid assay
US4100271A (en) * 1976-02-26 1978-07-11 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
US4188373A (en) * 1976-02-26 1980-02-12 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
DK185180A (en) * 1979-04-30 1980-10-31 Hoechst Ag Denatureringsbestandige aqueous proteinoploesninger and process for production thereof
US4297344A (en) * 1979-04-25 1981-10-27 Behringwerke Aktiengesellschaft Blood coagulation factors and process for their manufacture
US4357310A (en) * 1980-08-08 1982-11-02 Baxter Travenol Laboratories, Inc. Method and composition for reducing the nonspecific binding of radioiodinated protein hormones
US4474753A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Topical drug delivery system utilizing thermosetting gels
US4474752A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
EP0131864A2 (en) * 1983-07-13 1985-01-23 Hoechst Aktiengesellschaft Denaturation-resistant aqueous solutions of proteins, process for preparing them and their use
EP0193917A2 (en) * 1985-03-06 1986-09-10 American Cyanamid Company Water dispersible and water soluble carbohydrate polymer compositions for parenteral administration
US4623717A (en) * 1980-03-05 1986-11-18 Miles Laboratories, Inc. Pasteurized therapeutically active protein compositions
EP0211601A2 (en) * 1985-07-30 1987-02-25 International Minerals And Chemical Corporation Stabilization of growth promoting hormones
US4783441A (en) * 1979-04-30 1988-11-08 Hoechst Aktiengesellschaft Aqueous protein solutions stable to denaturation
EP0303746A1 (en) * 1987-08-21 1989-02-22 Mallinckrodt Group Inc. Stabilization of growth promoting hormones
US4812557A (en) * 1984-04-09 1989-03-14 Takeda Chemical Industries Stable composition of interleukin-2 and human serum albumin
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
US4857505A (en) * 1987-03-09 1989-08-15 American Cyanamid Company Sustained release compositions for parenteral administration and their use
US4857506A (en) * 1987-01-12 1989-08-15 American Cyanamid Company Sustained release growth hormone compositions for parenteral administration and their use
EP0332222A2 (en) * 1988-03-11 1989-09-13 Teikoku Seiyaku Co., Ltd. Intravaginal delivery of biologically active polypeptides
WO1989009614A1 (en) * 1988-04-15 1989-10-19 Genentech, Inc. Human growth hormone formulation
JPH01308235A (en) * 1988-06-03 1989-12-12 Yamanouchi Pharmaceut Co Ltd Human growth hormone for transnasal administration
US4917685A (en) * 1986-05-16 1990-04-17 International Minerals & Chem. Corp. Delivery device for the administration of stabilized growth promoting hormones
EP0374120A2 (en) * 1988-12-13 1990-06-20 Monsanto Company Comosition for controlled release of polypeptides
EP0406856A2 (en) * 1989-07-07 1991-01-09 Takeda Chemical Industries, Ltd. Stabilized FGF composition and production thereof
US4992419A (en) * 1987-05-09 1991-02-12 Boehringer Mannheim Gmbh Stabilized erythropoietin preparations
US5008244A (en) * 1989-05-15 1991-04-16 Pitman-Moore, Inc. Method for increasing fertility in animals
EP0433113A1 (en) * 1989-11-14 1991-06-19 FIDIA S.p.A. Stabilization and maintenance of the nerve growth factor biological activity by use of natural gangliosides or derivatives thereof
WO1991015509A1 (en) * 1990-04-04 1991-10-17 Sciosnova Inc. Methods and formulations for stabilizing fibroblast growth factor
WO1991018621A1 (en) * 1990-06-07 1991-12-12 Genentech, Inc. The combination of growth hormone and insulin-like growth factor-i enhances growth
WO1992017200A2 (en) * 1991-03-28 1992-10-15 Genentech, Inc. Stable growth hormone metal ion formulations
WO1993000109A1 (en) * 1991-06-28 1993-01-07 Genentech, Inc. Method of stimulating immune response using growth hormone
US5182258A (en) * 1989-03-20 1993-01-26 Orbon Corporation Systemic delivery of polypeptides through the eye
WO1993012811A1 (en) * 1991-12-20 1993-07-08 Novo Nordisk A/S A stabilized pharmaceutical formulation comprising growth hormone and asparagine
WO1993019776A1 (en) * 1992-04-03 1993-10-14 Kabi Pharmacia Ab Protein formulation comprising growth hormone
WO1993022335A1 (en) * 1992-04-30 1993-11-11 Cor Therapeutics, Inc. Stable polypeptide composition
WO1994003198A1 (en) * 1992-07-31 1994-02-17 Genentech, Inc. Human growth hormone aqueous formulation
US5317012A (en) * 1991-10-04 1994-05-31 The University Of Tennessee Research Corporation Human growth hormone induced improvement in depressed T4/T8 ratio
US5374620A (en) * 1990-06-07 1994-12-20 Genentech, Inc. Growth-promoting composition and its use
JPH0892125A (en) * 1994-09-21 1996-04-09 Nippon Chem Res Kk Aqueous medicine composition
US5597802A (en) * 1990-06-07 1997-01-28 Genentech, Inc. Method of formulating IGF-I with growth hormone
WO1997039768A1 (en) * 1996-04-24 1997-10-30 Novo Nordisk A/S A pharmaceutical formulation containing growth hormone, an amino acid and a non-ionic detergent
US5763394A (en) * 1988-04-15 1998-06-09 Genentech, Inc. Human growth hormone aqueous formulation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9007052D0 (en) 1990-03-29 1990-05-30 Skua Investments Ltd Pharmaceutical formulations
US5210017A (en) 1990-11-19 1993-05-11 Genentech, Inc. Ligand-mediated immunofunctional hormone binding protein assay method
US5981485A (en) * 1997-07-14 1999-11-09 Genentech, Inc. Human growth hormone aqueous formulation

Patent Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928137A (en) * 1971-10-20 1975-12-23 Mallinckrodt Inc Reagent formulation for uric acid assay
US4100271A (en) * 1976-02-26 1978-07-11 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
US4188373A (en) * 1976-02-26 1980-02-12 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
US4297344A (en) * 1979-04-25 1981-10-27 Behringwerke Aktiengesellschaft Blood coagulation factors and process for their manufacture
DK185180A (en) * 1979-04-30 1980-10-31 Hoechst Ag Denatureringsbestandige aqueous proteinoploesninger and process for production thereof
US4783441A (en) * 1979-04-30 1988-11-08 Hoechst Aktiengesellschaft Aqueous protein solutions stable to denaturation
US4623717A (en) * 1980-03-05 1986-11-18 Miles Laboratories, Inc. Pasteurized therapeutically active protein compositions
US4357310A (en) * 1980-08-08 1982-11-02 Baxter Travenol Laboratories, Inc. Method and composition for reducing the nonspecific binding of radioiodinated protein hormones
US4474753A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Topical drug delivery system utilizing thermosetting gels
US4474752A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
US4637834A (en) * 1983-07-13 1987-01-20 Hoechst Aktiengesellschaft Aqueous protein solutions which are stable towards denaturing, processes for their preparation and their use
EP0131864A2 (en) * 1983-07-13 1985-01-23 Hoechst Aktiengesellschaft Denaturation-resistant aqueous solutions of proteins, process for preparing them and their use
US4812557A (en) * 1984-04-09 1989-03-14 Takeda Chemical Industries Stable composition of interleukin-2 and human serum albumin
EP0193917A2 (en) * 1985-03-06 1986-09-10 American Cyanamid Company Water dispersible and water soluble carbohydrate polymer compositions for parenteral administration
EP0211601A2 (en) * 1985-07-30 1987-02-25 International Minerals And Chemical Corporation Stabilization of growth promoting hormones
US4917685A (en) * 1986-05-16 1990-04-17 International Minerals & Chem. Corp. Delivery device for the administration of stabilized growth promoting hormones
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
US4857506A (en) * 1987-01-12 1989-08-15 American Cyanamid Company Sustained release growth hormone compositions for parenteral administration and their use
US4857505A (en) * 1987-03-09 1989-08-15 American Cyanamid Company Sustained release compositions for parenteral administration and their use
US4992419A (en) * 1987-05-09 1991-02-12 Boehringer Mannheim Gmbh Stabilized erythropoietin preparations
EP0303746A1 (en) * 1987-08-21 1989-02-22 Mallinckrodt Group Inc. Stabilization of growth promoting hormones
EP0332222A2 (en) * 1988-03-11 1989-09-13 Teikoku Seiyaku Co., Ltd. Intravaginal delivery of biologically active polypeptides
WO1989009614A1 (en) * 1988-04-15 1989-10-19 Genentech, Inc. Human growth hormone formulation
US5763394A (en) * 1988-04-15 1998-06-09 Genentech, Inc. Human growth hormone aqueous formulation
US5096885A (en) * 1988-04-15 1992-03-17 Genentech, Inc. Human growth hormone formulation
JPH01308235A (en) * 1988-06-03 1989-12-12 Yamanouchi Pharmaceut Co Ltd Human growth hormone for transnasal administration
EP0374120A2 (en) * 1988-12-13 1990-06-20 Monsanto Company Comosition for controlled release of polypeptides
US5182258A (en) * 1989-03-20 1993-01-26 Orbon Corporation Systemic delivery of polypeptides through the eye
US5008244A (en) * 1989-05-15 1991-04-16 Pitman-Moore, Inc. Method for increasing fertility in animals
EP0406856A2 (en) * 1989-07-07 1991-01-09 Takeda Chemical Industries, Ltd. Stabilized FGF composition and production thereof
EP0433113A1 (en) * 1989-11-14 1991-06-19 FIDIA S.p.A. Stabilization and maintenance of the nerve growth factor biological activity by use of natural gangliosides or derivatives thereof
WO1991015509A1 (en) * 1990-04-04 1991-10-17 Sciosnova Inc. Methods and formulations for stabilizing fibroblast growth factor
WO1991018621A1 (en) * 1990-06-07 1991-12-12 Genentech, Inc. The combination of growth hormone and insulin-like growth factor-i enhances growth
US5126324A (en) * 1990-06-07 1992-06-30 Genentech, Inc. Method of enhancing growth in patients using combination therapy
US5597802A (en) * 1990-06-07 1997-01-28 Genentech, Inc. Method of formulating IGF-I with growth hormone
US5374620A (en) * 1990-06-07 1994-12-20 Genentech, Inc. Growth-promoting composition and its use
WO1992017200A2 (en) * 1991-03-28 1992-10-15 Genentech, Inc. Stable growth hormone metal ion formulations
WO1993000109A1 (en) * 1991-06-28 1993-01-07 Genentech, Inc. Method of stimulating immune response using growth hormone
US5317012A (en) * 1991-10-04 1994-05-31 The University Of Tennessee Research Corporation Human growth hormone induced improvement in depressed T4/T8 ratio
WO1993012811A1 (en) * 1991-12-20 1993-07-08 Novo Nordisk A/S A stabilized pharmaceutical formulation comprising growth hormone and asparagine
US5567677A (en) * 1992-04-03 1996-10-22 Pharmacia Ab Protein formulation comprising growth hormone
WO1993019776A1 (en) * 1992-04-03 1993-10-14 Kabi Pharmacia Ab Protein formulation comprising growth hormone
WO1993022335A1 (en) * 1992-04-30 1993-11-11 Cor Therapeutics, Inc. Stable polypeptide composition
WO1994003198A1 (en) * 1992-07-31 1994-02-17 Genentech, Inc. Human growth hormone aqueous formulation
JPH0892125A (en) * 1994-09-21 1996-04-09 Nippon Chem Res Kk Aqueous medicine composition
WO1997039768A1 (en) * 1996-04-24 1997-10-30 Novo Nordisk A/S A pharmaceutical formulation containing growth hormone, an amino acid and a non-ionic detergent

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
Becker et al., "Chemical, physical, and biological characterization of a dimeric form of biosynthetic human growth hormone" Biotechnology and Applied Biochemistry 9:478-487 (1987).
Becker et al., Chemical, physical, and biological characterization of a dimeric form of biosynthetic human growth hormone Biotechnology and Applied Biochemistry 9:478 487 (1987). *
Brange Jens et al., "Galenics of Insulin," Springer-Verlag, Berlin, Heidelberg (1987) pp. 67-68.
Brange Jens et al., Galenics of Insulin, Springer Verlag, Berlin, Heidelberg (1987) pp. 67 68. *
Chawla et al., "Aggregation of Insulin, containing surfactants, in contact with different materials," Diabetes (1985) 34:420-424.
Chawla et al., Aggregation of Insulin, containing surfactants, in contact with different materials, Diabetes (1985) 34:420 424. *
Clarke et al., "Method of formulating IGF-1 with growth hormone," Journal of Biotechnology Advances, vol. 15, No. 3-4, p785.
Clarke et al., Method of formulating IGF 1 with growth hormone, Journal of Biotechnology Advances, vol. 15, No. 3 4, p785. *
Dellacha et al., "Physicochemical behaviour and biological activity of bovine growth hormone in acidic solution,"Biochemical Et Biophysica ACTA (1968) 168:95-105.
Dellacha et al., Physicochemical behaviour and biological activity of bovine growth hormone in acidic solution, Biochemical Et Biophysica ACTA (1968) 168:95 105. *
Lougheed et al., "Physical Stability of Insulin Formulations," 32:424-432 (1983).
Lougheed et al., Physical Stability of Insulin Formulations, 32:424 432 (1983). *
Manning et al., "Stability of Protein Pharmaceuticals," Pharmaceutical Research, vol. 6, No. 11, pp. 903-917 (1989).
Manning et al., Stability of Protein Pharmaceuticals, Pharmaceutical Research, vol. 6, No. 11, pp. 903 917 (1989). *
Pearlman et al. Current Communications in Molecular Biology, D. Marshak, D. Liu pp. 23 30 (1989). *
Pearlman et al. Current Communications in Molecular Biology, D. Marshak, D. Liu pp. 23-30 (1989).
Physician s Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1049 1050 (1992). *
Physician s Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1193 1194 (1988). *
Physician s Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1266 1267 (1992). *
Physician's Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1049-1050 (1992).
Physician's Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1193-1194 (1988).
Physician's Desk Reference, Orawell, NJ:Medical Economics Co. pp. 1266-1267 (1992).
Research Disclosure RD 370013, "Stabilised protein formulations, particularly, for somatotropin implants-contain stabilising polyol, buffer, wetting agent and alkali metal halide" (Feb. 10, 1995).
Research Disclosure RD 370013, Stabilised protein formulations, particularly, for somatotropin implants contain stabilising polyol, buffer, wetting agent and alkali metal halide (Feb. 10, 1995). *
Skottner et al., "Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin-like growth factor I" Endocrinology 124(5):2519-2526 (1989).
Skottner et al., Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin like growth factor I Endocrinology 124(5):2519 2526 (1989). *
The Merck Index, Rahway, NJ:Merck & Co. Inc. p. 1203, entry No. 7537 (1989). *
The Merck Index, Rahway, NJ:Merck & Co. Inc. p. 983, entry No. 7342 (1976). *
Thurow et al., "Stabilisation of dissolved proteins against denaturation at hydrophobic interfaces," Diabetologia, 27:212-218 (1984).
Thurow et al., Stabilisation of dissolved proteins against denaturation at hydrophobic interfaces, Diabetologia, 27:212 218 (1984). *
Yoshihiro, "Making preparations: Formulations," Journal Iyakuhin Kenkyu, vol. 20, No. 3, pp. 584-586 (1989).
Yoshihiro, Making preparations: Formulations, Journal Iyakuhin Kenkyu, vol. 20, No. 3, pp. 584 586 (1989). *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050209144A1 (en) * 1998-04-28 2005-09-22 Nps Allelix Corporation Protein formulations
US6905886B2 (en) 2000-08-11 2005-06-14 Quest Diagnostics Investments Incorporated Preservative solutions
US20020160353A1 (en) * 2000-08-11 2002-10-31 Quest Diagnostics Investments Incorporated Preservative solutions
US6387711B1 (en) * 2000-08-11 2002-05-14 Quest Diagnostics Investments Incorporated Liquid intact parathyroid hormone (PTH) standards
GB2371227A (en) * 2001-01-10 2002-07-24 Grandis Biotech Gmbh Crystallisation - resistant aqueous growth hormone formulations
US7271150B2 (en) 2001-05-14 2007-09-18 United States Of America, Represented By The Secretary, Department Of Health And Human Services Modified growth hormone
US20110135614A1 (en) * 2001-05-14 2011-06-09 The United States Of America, Represented By, Depa Rtment Of Health Modified growth hormone
US20040158046A1 (en) * 2001-05-14 2004-08-12 Loh Yoke Peng Modified growth hormone
US7888070B2 (en) 2001-05-14 2011-02-15 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Nucleic acids encoding growth hormone with a modified RSP sorting signal
US8252739B2 (en) 2001-12-21 2012-08-28 Human Genome Sciences, Inc. Albumin fusion proteins
US8993517B2 (en) 2001-12-21 2015-03-31 Human Genome Sciences, Inc. Albumin fusion proteins
US9296809B2 (en) 2001-12-21 2016-03-29 Human Genome Sciences, Inc. Albumin fusion proteins
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins
US8071539B2 (en) 2001-12-21 2011-12-06 Human Genome Sciences, Inc. Albumin fusion proteins
US8513189B2 (en) 2001-12-21 2013-08-20 Human Genome Sciences, Inc. Albumin fusion proteins
US9221896B2 (en) 2001-12-21 2015-12-29 Human Genome Sciences, Inc. Albumin fusion proteins
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
WO2003079991A3 (en) * 2002-03-20 2003-12-18 Advanced Inhalation Res Inc Method for administration of growth hormone via pulmonary delivery
US20060039987A1 (en) * 2002-03-20 2006-02-23 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
WO2003079991A2 (en) * 2002-03-20 2003-10-02 Advanced Inhalation Research, Inc. Method for administration of growth hormone via pulmonary delivery
US20040009231A1 (en) * 2002-03-20 2004-01-15 Advanced Inhalation Research, Inc. hGH (human growth hormone) formulations for pulmonary administration
US20060165733A1 (en) * 2002-07-09 2006-07-27 Michael Betz Liquid formulations with high concentration of hunan growth hormone (hgh) comprising phenol
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US20040209804A1 (en) * 2002-12-31 2004-10-21 Chandrika Govardhan Human growth hormone crystals and methods for preparing them
EP2460530A2 (en) 2002-12-31 2012-06-06 Althea Technologies, Inc. Human growth hormone crystals and methods for preparing them
US9376479B2 (en) 2002-12-31 2016-06-28 Anjinomoto Althea, Inc. Human growth hormone crystals and methods for preparing them
WO2004060310A2 (en) 2002-12-31 2004-07-22 Altus Pharmaceuticals Inc. Human growth hormone crystals and methods for preparing them
WO2005063298A1 (en) 2003-12-23 2005-07-14 Pharmacia Corporation Stable growth hormone liquid formulation
US20080113912A1 (en) * 2004-12-22 2008-05-15 Ambrx, Inc. Formulations of Human Growth Hormone Comprising a Non-Naturally Encoded Amino Acid
US20060135427A1 (en) * 2004-12-22 2006-06-22 Ambrx, Inc. Formulations of human growth hormone comprising a non-naturally encoded amino acid
US8163695B2 (en) * 2004-12-22 2012-04-24 Ambrx Formulations of human growth hormone comprising a non-naturally encoded amino acid
US7816320B2 (en) * 2004-12-22 2010-10-19 Ambrx, Inc. Formulations of human growth hormone comprising a non-naturally encoded amino acid at position 35
US20090023629A1 (en) * 2005-12-23 2009-01-22 Altus Pharmaceuticals Inc. Compositions comprising polycation-complexed protein crystals and methods of treatment using them
EP2738257A1 (en) 2007-05-22 2014-06-04 Amgen Inc. Compositions and methods for producing bioactive fusion proteins
US8420779B2 (en) 2007-05-22 2013-04-16 Amgen Inc. Compositions and methods for producing bioactive fusion proteins
US9238878B2 (en) 2009-02-17 2016-01-19 Redwood Bioscience, Inc. Aldehyde-tagged protein-based drug carriers and methods of use
US9879249B2 (en) 2009-02-17 2018-01-30 Redwood Bioscience, Inc. Aldehyde-tagged protein-based drug carriers and methods of use
US9540438B2 (en) 2011-01-14 2017-01-10 Redwood Bioscience, Inc. Aldehyde-tagged immunoglobulin polypeptides and methods of use thereof
US20150118255A1 (en) * 2012-03-30 2015-04-30 Hanmi Science Co., Ltd Liquid formulation of highly concentrated long-acting human growth hormone conjugate

Also Published As

Publication number Publication date Type
US20090163419A1 (en) 2009-06-25 application
US20070027083A1 (en) 2007-02-01 application
US20050272657A1 (en) 2005-12-08 application
US20030013653A1 (en) 2003-01-16 application
US6448225B2 (en) 2002-09-10 grant
US20110230408A1 (en) 2011-09-22 application
US20010007858A1 (en) 2001-07-12 application
US20130165378A1 (en) 2013-06-27 application

Similar Documents

Publication Publication Date Title
US5681814A (en) Formulated IGF-I Composition
US5374620A (en) Growth-promoting composition and its use
US4496537A (en) Biologically stable alpha-interferon formulations
US20030113316A1 (en) Stable lyophilized pharmaceutical formulation of IgG antibodies
US5919443A (en) Stable lyophilized pharmaceutical preparations of G-CSF
US4847079A (en) Biologically stable interferon compositions comprising thimerosal
US5496801A (en) Parathyroid hormone formulation
US6770623B1 (en) Stabilized teriparatide solutions
US6250469B1 (en) Formulations for protection of peg-interferon alpha conjugates
EP0448146A1 (en) Stabilized gonadotropin containing preparations
US6696056B1 (en) Pharmaceutical compositions of erythropoietin
US5766582A (en) Stable, aqueous alfa interferon solution formulations
WO2013164837A1 (en) Pharmaceutical formulations of tnf-alpha antibodies
EP0736303A2 (en) Interferon solution
WO1998028007A1 (en) Stable liquid interferon formulations
US6277828B1 (en) Pharmaceutical formulations of nerve growth factor
US20030104983A1 (en) Stable insulin formulations
WO2001049314A2 (en) Glp-2 formulations
US5898030A (en) hGH containing pharmaceutical compositions
WO1992017200A2 (en) Stable growth hormone metal ion formulations
EP0193372A2 (en) Intranasally applicable powdery pharmaceutical composition
WO2007037607A1 (en) Hfsh aqueous formulation
US20070292391A1 (en) Stabilized Interferon Liquid Formulations
WO2001005355A2 (en) Formulations for il-11
WO1997039768A1 (en) A pharmaceutical formulation containing growth hormone, an amino acid and a non-ionic detergent

Legal Events

Date Code Title Description
FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12